Our objective is to understand the functions and coupling modes of bicarbonate and proton transporters in transepithelial ion transport. HCO 3 and H are generated from H2 O and CO2 via carbonic anhydrase activity and coupled to transport of other ions by Na/H exchangers (NHE1-4), Cl/HCO exchangers (AE1-4, PAT1, DRA), Na- HCO3 cotransporters (NBCe1, NBCe2), H,K-ATPases, and others. In coupled systems, they mediate gastric acid secretion; maintain fluidity and pH of lumenal contents in intestine; recover ions and water in colon; and control acid-base, electrolyte, and fluid excretion by the kidney. To study these issues, we are utilizing mice with genetic ablation of various acid-base transporters. In Aim 1, the mechanisms of HCl secretion in stomach and maintenance of parietal cell (PC) viability will be analyzed by testing the hypotheses that AE2 is the major basolateral Cl/HCO3 exchanger that balances HCl secretion; that AE2 is coupled with the basolateral NHE4 Na/ H exchanger for volume loading; that NHE4 and NHE2 are required for PC viability; and that CLIC intracellular Cl channels are required for acid secretion. Aim 2 will test the hypotheses that reductions in apical NaCl absorption in the intestinal tract involving coupled Cl/HCO (PAT1, DRA) and Na/H (NHE3) exchange can correct perturbations of lumenal fluidity and pH in Cystic Fibrosis (CF) and lessen the severity of CF intestinal disease; and that basolateral AE2 in concert with apical NHE3 and/or colonic H,K-ATPase mediates Na-HCO3 and K-HCO3 absorption in the intestinal tract. Aim 3 will test the hypotheses that NBCe1 and the AE4 Cl/HCO exchanger, each a component of coupled systems in different segments of the kidney, contribute to Na-HCO absorption; that NBCe2 mediates a unique Na-HCO secretory function in the collecting duct; and that the colonic H,K-ATPase contributes to K-HCO3 absorption in the collecting duct. These studies will expand our understanding of the coupling modes that allow these transporters to mediate both absorptive and secretory functions. They have clinical relevance to gastroesophageal reflux and other diseases involving acid secretion; diarrheas; cystic fibrosis intestinal disease; and renal mechanisms for recovery from disorders of systemic acid-base, electrolyte, and fluid-volume homeostasis caused by gastrointestinal and other diseases.